Compounds and compositions for treating cancer

ABSTRACT

The invention relates to compounds and composition for the treatment and prevention of cancer. The invention also covers all diseases that may be treated by selective modulation of levels of reactive oxygen species in diseased cells versus normal cells. Methods for the preparation and administration of such compositions are also disclosed.

CLAIM OF PRIORITY

This application claims priority to U.S. Provisional Application Ser.No. 61/275,754, filed Sep. 2, 2009 and entitled “COMPOUNDS ANDCOMPOSITIONS FOR TREATING CANCER” which is incorporated by reference inits entirety.”

FIELD OF THE INVENTION

The invention relates to compounds and composition for the treatment andprevention of cancer. The invention also covers all diseases that may betreated by selective modulation of levels of reactive oxygen species indiseased cells versus normal cells. Methods for the preparation andadministration of such compositions are also disclosed.

BACKGROUND OF THE INVENTION

The present invention relates to compounds and compositions for thetreatment and prevention of cancer, or decreasing the intensity orduration of cancer. The invention also covers all diseases that may betreated by selective modulation of levels of reactive oxygen species indiseased cells versus normal cells.

All living aerobic cells are normally exposed to some reactive oxygenspecies (ROS) but if ROS levels rise, oxidative stress (OS) occurs,which results in oxygen and oxygen-derived oxidants, and in turnincreases the rates of cellular damage. Cells are exposed to bothendogenous and exogenous sources of ROS. At high levels, ROS can lead toimpaired physiological function through cellular damage of DNA,proteins, lipids, and other macromolecules, which can lead to certainhuman pathologies including cancers, neurodegenerative disorders, andcardiovascular disease, as well as aging. Moreover, ROS are important inmediating apoptosis.

Selectively increasing levels of ROS in cancer cells and not normal cellmay be a safe and effective method for treating cancer. FIG. 6 showscancer therapies targeting various hallmarks of cancer.

Reducing ROS leads to treatment of neurodegenerative diseases,inflammation and for the treatment of a broad range of disordersincluding, neurodegenerative diseases, chronic inflammatory diseases,inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiplesclerosis, endotoxin shock, osteoporosis, Alzheimer's disease,congestive heart failure and skin disease.

There remains a need for compounds which can increase ROS in cancercells while reducing or maintaining ROS levels in normal cells.

SUMMARY OF THE INVENTION

Compounds and compositions that are useful for the treatment andprevention of cancer are provided. The present invention encompassescompounds having the following formula IA, or salts, derivatives, ormixtures thereof:

or a pharmaceutically acceptable salt or pharmaceutically acceptablederivative thereof, wherein:

-   Ring A is selected from the group consisting of one or more    monocyclic aryl, one or more heteroaryl, a 3-7 membered saturated or    partially unsaturated carbocyclic ring, an 8-10 membered bicyclic    saturated, partially unsaturated or aryl ring, a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated    or partially unsaturated heterocyclic ring having 1-3 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, a 7-10    membered bicyclic saturated or partially unsaturated heterocyclic    ring having 1-5 heteroatoms independently selected from nitrogen,    oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring    having 1-5 heteroatoms independently selected from nitrogen, oxygen,    or sulfur;-   each R¹, R², and R³ is independently selected from the group    consisting of hydrogen, halogen, deuterium, CF₃, CN, OR, SR, NRR,    NRCOR, NRCONRR, NRCO₂R, COR, CO₂R, NOR, NO₂, CONRR, OC(O)NRR, SO₂R,    SO₂NRR, NRSO₂R, NRSO₂NRR, C(O)C(O)R, or C(O)CH₂C(O)R, alkyl, aryl,    heteroaryl and morpholino, wherein either R¹ and R², or R² and R³    are optionally taken together to form a 4-8 membered saturated,    partially unsaturated, or fully unsaturated ring having 0-3    heteroatoms independently selected from nitrogen, oxygen, or sulfur;    and z is 0, 1 or 2;-   each R is independently selected from hydrogen or an optionally    substituted C₁-C₄ aliphatic moiety, wherein:-   or alternately, two R moieties bound to the same nitrogen atom are    optionally taken together with the nitrogen atom to form a 3-7    membered saturated, partially unsaturated, or fully unsaturated ring    having 1-2 additional heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   B is selected from:

wherein

-   R4, R5, R6 and R7 are independently selected from a substituted or    unsubstituted C₁ to C₁₂ alkyl, a substituted or unsubstituted C₁ to    C₁₂ alkenyl or a substituted or unsubstituted C₁ to C₁₂ alkynyl;-   X is O, S; and-   C is a saturated or unsaturated heteroaryl or a saturated or    unsaturated C1 to C7 heterocyclic containing one or more hetero    atoms wherein the heteroatoms are independently selected from N, O    or S;-   or C a fused ring; and-   wherein any one or more H is optionally replaced by a deuterium.

The compounds of the present invention may be produced usingpiperlongumine as a starting material yet offer numerous advantages overpiperlongumine. In the course of the experimental investigations, it wasfound that more than 0.25 mg/ml of piperlongumine in DMSO wasprecipitated out when diluted 1:10 in phosphate buffered saline orwater. It was also found that piperlongumine is soluble in water at 0.1mg/mL. The compounds of the instant invention are highly soluble inwater at concentration of at least 25 mg/mL facilitating pharmaceuticalpreparation and delivery. Many chemotherapeutic agents transientlyincrease ROS levels in both cancer cells and normal cells. In contrast,the compounds of the instant invention have a large therapeutic windowand do not increase ROS or cause DNA damage in normal cells. Compared tocurrent standards such as etoposide, 5-fluorouracil, cisplatin andtaxol, the drug is comparable in its effect on net cancer cell growth(melanoma, ovarian, renal, glioblastoma, drug-resistant non-small celllung cancer cell lines) as a percent of control.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of compounds on pancreatic cells

FIG. 2 shows viability of normal breast epithelium in the presence ofcompounds of the invention.

FIG. 3 shows the effect of compounds on EJ Bladder Carcinoma cells

FIG. 4 shows the effect of compounds on pancreatic cells

FIG. 5 shows the effect of SP2007 and SP83 on bladder tumorxenograft-bearing mice

FIG. 6 shows cancer therapies targeting various hallmarks of cancer.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Definitions

The term “about” or “approximately” means within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean within 1 or more than 1 standard deviations,per practice in the art. Alternatively, “about” with respect to theformulations can mean a range of up to 10%, preferably up to 5%.

The terms “alkyl”, “alkenyl”, “alkoxy”, “alkylene”, “alkenylene”,“alkenyl”, “alkyl(arylene)”, “alkynyl”, and “aryl(alkylene)” include,but are not limited to, linear and branched alkyl, alkenyl, alkoxy,alkylene, alkenylene, alkyl(arylene), and aryl(alkylene) groups,respectively.

The phrase “pharmaceutically acceptable” refers to compounds orcompositions that are physiologically tolerable and do not typicallyproduce an allergic or similar untoward reaction, such as gastric upset,dizziness and the like, when administered to a mammal.

An “effective amount of compound” means the amount of compound, salt orsalts, or (including its solvates, active metabolites, prodrugs, orracemates or enantiomers thereof (assuming the salt has a chiralcenter)) that, when administered to a mammal for treating or preventinga state, disorder or condition is sufficient to effect such treatment orprevention. The “effective amount” will vary depending on the activeingredient, the state, disorder, or condition to be treated and itsseverity, and the age, weight, physical condition and responsiveness ofthe mammal to be treated. According to one embodiment of the presentinvention, a therapeutically effective amount of a compound is an amounteffective to treat any one of the above mentioned disorders. Thecompound or its salt or salts may be augmented with a second medication(such as a chemotherapeutic agent, or adjunctive chemotherapeutic agentto treat any of the aforementioned disorders, such as malignancies).

An “effective amount of the pharmaceutical formulation” is an amount ofthe pharmaceutical formulation described which is effective to treat orprevent a condition in a subject to whom it is administered over someperiod of time, e.g., provides a therapeutic effect during a desireddosing interval. Generally, an effective amount of the pharmaceuticalformulation includes amounts of compound its salt or salts to treat orprevent the desired condition over a desired period of time.

As used herein, the term “treat” includes one or more of the following:

-   -   (a) arresting, delaying the onset (i.e., the period prior to        clinical manifestation of a disorder) and/or reducing the risk        of developing or worsening a disorder;    -   (b) relieving or alleviating at least one symptom of a disorder        in a mammal, including for example, cancer; or    -   (c) relieving or alleviating the intensity and/or duration of a        manifestation of a disorder experienced by a mammal including,        but not limited to, those which are in response to a given        stimulus (e.g., pressure, tissue injury or cold temperature).

The term “treat” also includes prophylactically preventing, curing,healing, alleviating, relieving, altering, remedying, ameliorating,improving, or affecting a condition (e.g., a disease), the symptoms ofthe condition, or the predisposition toward the condition.

The term “sustained release” as used herein refers to the release of anactive ingredient over an extended period of time leading to lower peakplasma concentrations and a prolonged T_(max) as compared to “immediaterelease” formulations of the same active ingredient.

The term “bioavailability” refers to the rate and extent to which theactive ingredient (compound its salt or salts) or active moiety isabsorbed from a drug product and becomes systematically available.

The term “polymorph” refers to crystallographically distinct forms of asubstance.

The term “hydrate” as used herein includes, but is not limited to, (i) asubstance containing water combined in the molecular form and (ii) acrystalline substance containing one or more molecules of water ofcrystallization or a crystalline material containing free water.

The term “solvate” as used herein includes, but is not limited to, amolecular or ionic complex of molecules or ions of a solvent withmolecules or ions of a compound or its salt or salts.

The term “adjunctive chemotherapeutic agent” includes agents whichtreat, alleviate, relieve, or amelliorate the side effects ofchemotherapeutic agents. Such agents include those which modify bloodcell growth and maturation. Examples of adjunctive chemotherapeuticagents include, but are not limited to, filgrastim and erythropoietin.

The term “salt” includes compound salt or salts, complexes and activemetabolites, prodrugs, racemates, enantiomers, and hydrates thereof.

The term “chemotherapeutic agent” includes any agent which treats,prevents, cures, heals, alleviates, relieves, alters, remedies,ameliorates, improves, or affects malignancies and their metastasis.Examples of such agents (also known as “antineoplastic agents”) include,but are not limited to, prednisone, fluorouracil (e.g., 5-fluorouracil(5-FU)), anastrozole, bicalutamide, carboplatin, cisplatin,chlorambucil, docetaxel, doxorubicin, flutamide, interferon-alpha,letrozole, leuprolide, megestrol, mitomycin, paclitaxel, plicamycin(Mithracin™), tamoxifen, thiotepa, topotecan, valrubicin, vinylastin,vincristine, and any combination of any of the foregoing. Furtherexamples are provided herein.

The term ‘Hydrogen” or “H” includes any form of hydrogen, includingdeuterium.

Compounds

The present invention provides compounds and compositions which treatand prevent cancer. Compounds of the present invention include thosehaving the following formula I:

or a pharmaceutically acceptable salt or pharmaceutically acceptablederivative thereof, wherein:

-   Ring A is selected from the group consisting of one or more    monocyclic aryl, one or more heteroaryl, a 3-7 membered saturated or    partially unsaturated carbocyclic ring, an 8-10 membered bicyclic    saturated, partially unsaturated or aryl ring, a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated    or partially unsaturated heterocyclic ring having 1-3 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, a 7-10    membered bicyclic saturated or partially unsaturated heterocyclic    ring having 1-5 heteroatoms independently selected from nitrogen,    oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring    having 1-5 heteroatoms independently selected from nitrogen, oxygen,    or sulfur;-   each R¹, R², and R³ independently selected from the group consisting    of hydrogen, halogen, deuterium, CF₃, CN, OR, SR, NRR, NRCOR,    NRCONRR, NRCO₂R, COR, CO₂R, NOR, NO₂, CONRR, OC(O)NRR, SO₂R, SO₂NRR,    NRSO₂R, NRSO₂NRR, C(O)C(O)R, or C(O)CH₂C(O)R, alkyl, aryl,    heteroaryl and morpholino, wherein either R¹ and R², or R² and R³    are optionally taken together to form a 4-8 membered saturated,    partially unsaturated, or fully unsaturated ring having 0-3    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   each R is independently selected from hydrogen or an optionally    substituted C₁-C₄ aliphatic moiety (i.e. alkyl, alkenyl, or    alkynyl), wherein:-   or alternately, two R moieties bound to the same nitrogen atom are    optionally taken together with the nitrogen atom to form a 3-7    membered saturated, partially unsaturated, or fully unsaturated ring    having 1-2 additional heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   B is selected from:

wherein

-   R4, R5, R6 and R7 are independently selected from a substituted or    unsubstituted C₁ to C₁₂ alkyl, a substituted or unsubstituted C₁ to    C₁₂ alkenyl or a substituted or unsubstituted C₁ to C₁₂ alkynyl;-   X is O, S; and-   C is a saturated or unsaturated heteroaryl or a saturated or    unsaturated C1 to C7 heterocyclic containing one or more hetero    atoms wherein the heteroatoms are independently selected from N, O    or S;-   or C is a fused ring; and-   wherein any one or more H is optionally replaced by a deuterium.

In another embodiment, the compounds of the invention are compounds ofFormula I above wherein ring A is selected from:

wherein the ring carries R¹, R² and R³ as defined above;

-   wherein Y is N, O or S; and-   C is selected from:

wherein the ring is optionally substituted with one or more R¹⁰ and R¹¹,wherein R¹⁰ and R¹¹ are independently selected from a substituted orunsubstituted C₁ to C₁₂ alkyl, a substituted or unsubstituted C₁ to C₁₂alkenyl or a substituted or unsubstituted C₁ to C₁₂ alkynyl, an ether, athioether, aryl,

-   -   n is 1, 2 or 3;    -   X₁ is O or S;

In a preferred embodiment, the compound of formula I is represented bythe following compounds:

In one embodiment, the compounds of the present invention interact withproteins to increase ROS in cancer cells but not in normal cells. In oneembodiment, the compounds of the present invention increase phosphor-JNKlevels. In one embodiment, the compounds of the present inventionincrease p53 activity. In one embodiment, the compounds of the presentinvention increase p21 activity. In one embodiment, the compounds of thepresent invention decrease pro-survival gene activity. In oneembodiment, the compounds of the present invention induce apoptosis incancer cell lines.

In another embodiment, the one or more compounds of the instantinvention are used to treat cancer. Another embodiment includes a methodfor increasing apoptosis by administering a compound of the instantinvention. Another embodiment includes a method for increasing p53activity by administering one or more compounds of the instantinvention. Another embodiment includes a method for increasing p21activity by administering one or more compounds of the instantinvention. Another embodiment includes a method of preferentiallyinducing DNA damage in cancer cells by administering one or morecompounds of the instant invention. Another embodiment is a method ofsuppressing DNA damage in normal cells by administering one or morecompounds of the instant invention.

In another embodiment, the invention provides a method for improving theexpression of proteins associated with normal cell survival. In anotherembodiment, the invention provides for a method of sparing normal cellswhile killing cancer cells.

In another embodiment, the invention provides a method of administeringa compound of the instant invention at a dose of about 100 mg/kg toabout 3000 mg/kg. In another embodiment the invention provides a methodof administering a compound of the instant invention at a dose of about2.5 mg/kg to about 10 mg/kg. In some embodiments, a therapeuticallyeffective amount is less than 50 mg/kg, such as less than 45 mg/kg, lessthan 40 mg/kg, less than 35 mg/kg, less than 30 mg/kg, less than 25mg/kg, less than 20 mg/kg or less than 15 mg/kg. In some embodiments, atherapeutically effective amount is less than 10 mg/kg, such as lessthan 9 mg/kg, less than 8 mg/kg, less than 7 mg/kg, less than 6 mg/kg,less than 5 mg/kg, less than 4 mg/kg, less than 3 mg/kg or less than 2mg/kg. In some embodiments, a therapeutically effective amount is lessthan 1.5 mg/kg, such as less than 1.4 mg/kg, less than 1.3 mg/kg, lessthan 1.2 mg/kg, less than 1.1 mg/kg, less than 1 mg/kg, less than 0.9mg/kg, less than 0.8 mg/kg, less than 0.7 mg/kg, less than 0.6 mg/kg,less than 0.5 mg/kg, less than 0.4 mg/kg, less than 0.3 mg/kg, less than0.2 mg/kg or less than 0.1 mg/kg.

In another aspect, the invention provides a method for inhibiting cellproliferation. In some embodiments, the method for inhibiting cellproliferation comprises contacting a cell with an effective amount of acomposition comprising a compound of the invention to inhibit theproliferation of the cell. In some embodiments, the method furthercomprises contacting the cells with a compound of the invention and achemotherapeutic agent. In another aspect, the invention provides amethod for increasing apoptosis of a cell or in a population of cells.In some embodiments, the method for increasing apoptosis of a cell or ina population of cells, the method comprises contacting the cell orpopulation of cells with an effective amount of a composition comprisinga compound of the invention to increase apoptosis in the cell orpopulation of cells. In some embodiments, the number of apoptotic cellsin a population of cells is increased by at least two-fold. In someembodiments, the number of apoptotic cells in a population of cells isincreased by at least five-fold. In some embodiments, the number ofapoptotic cells in a population of cells is increased by at leastten-fold. In some embodiments, the method further comprises contactingthe cells with a compound of the invention and a chemotherapeutic agent.

In another embodiment one or more compounds of the instant invention areadministered with one or more chemotherapeutic agent. In anotherembodiment, one or more compounds of the instant invention areadministered prior to one or more chemotherapeutic agents. In anotherembodiment, one or more compounds of the instant invention areadministered following one or more chemotherapeutic agents.

Chemotherapeutic agents include, but are not limited to an agent whichis administered to a subject for the purpose of treating a cancer.Chemotherapeutic agents include, but are not limited toantiproliferative compounds, anti-neoplastic compounds, anti-cancersupplementary potentiating agents and radioactive agents. One ofordinary skill in the art is familiar with a variety of chemotherapeuticagents, or can find those agents in the routine art, which are used inthe medical arts to treat cancer.

Chemotherapeutic agents include, but are not limited to, the followingsub-classes of compounds: Antineoplastic agents such as: Acivicin;Aclarubicin; Acodazole Hydrochloride; Acronine; Adozelesin; Adriamycin;Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate;Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase;Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Buniodepa;Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin;Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan;Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin;Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol;Chlorombucil; Cirolemycin; Cisplatin; Cladribine; Crisnatol Mesylate;Cyclophosphamide; Cytarabine; Dacarbazine; DACA(N-[2-(Dimethyl-amino)ethyl]acridine-4-carboxamide); Dactinomycin;Daunorubicin Hydrochloride; Daunomycin; Decitabine; Dexormaplatin;Dezaguanine; Dezaguanine Ifesylate; Diaziquone; Docetaxel; Doxorubicin;Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate;Dromostanolone Propionate; Duazomycin; Edatrexate; EflornithineHydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine;Epirubicin 30 Hydrochloride; Erbulozole; Esorubicin Hydrochloride;Estramustine; Estramustine Phosphate Sodium; Etanidazole; Ethiodized OilI 131; Etoposide; Etoposide Phosphate; Etoprine; FadrozoleHydrochloride; Fazarabine; Fenretinide; Floxuridine; FludarabinePhosphate; Fluorouracil; 5-FdUMP; Fluorocitabine; Fosquidone; FostriecinSodium; Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198;Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmofosine;Interferon Alfa-2a; Interferon Alfa-2b; Interferon Alfa-n1; InterferonAlfa-n3; Interferon Beta-1a; Interferon Gamma-1b; Iproplatin; IrinotecanHydrochloride; Lanreotide Acetate; Letrozole; Leuprolide Acetate;Liarozole Hydrochloride; 5 Lometrexol Sodium; Lomustine; LosoxantroneHydrochloride; Masoprocol; Maytansine; Mechlorethamine Hydrochloride;Megestrol Acetate; Melengestrol Acetate; Melphalan; Menogaril;Mercaptopurine; Methotrexate; Methotrexate Sodium; Metoprine;Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin;Mitomycin, Mitosper; Mitotane; Mitoxantrone Hydrochloride; MycophenolicAcid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; PaclitaxelPegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate;Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride;Plicamycin; Plomestane; Porfimer Sodium; Porfiromycin; Prednimustine;Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride;Pyrazofurin; Riboprine; Rogletimide; Safingol; Safingol Hydrochloride;Semustine; Simtrazene; Sparfosate Sodium; Sparsomycin; SpirogermaniumHydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin;Strontium Chloride Sr 89; Sulofenur; Talisomycin; Taxane; Taxoid;Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride; Temoporfin;Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine;Thiotepa; Thymitaq; Tiazofurin; Tirapazamine; Tomudex; TOP-53; TopotecanHydrochloride; Toremifene Citrate; Trestolone Acetate; TriciribinePhosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin;Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide;Verteporfin; Vinblastine; Vinblastine Sulfate; Vincristine; VincristineSulfate, Vindesine; Vindesine Sulfate; Vinepidine Sulfate; VinglycinateSulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; VinrosidineSulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin;Zorubicin Hydrochloride; 2-Chlorodeoxyadenosine; 2′-Deoxyformycin;9-aminocamptothecin; raltitrexed; N-propargyl-5,8-dideazafolic acid,2-chloro-2′-arabino-fluoro-2′-deoxyadenosine;2-chloro-2′-deoxyadenosine; anisomycin; trichostatin A; hPRL-G129R;CEP-751; linomide; Piritrexim Isethionate; Sitogluside; TamsulosinHydrochloride and Pentomone. Anti-neoplastic compounds include, but arenot limited to 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil;abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin;aldesleukin; ALL-TK antogonists; altretamine; ambamustine; amidox;amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide;anastrozole; andrographolide; angiogenesis inhibitors; antagonist D;antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1;antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;antisense oligonucleotides; aphidicolin glycinate; apoptosis genemodulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives (e.g.,10-hydroxy-camptothecin); canarypox IL-2; capecitabine;carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700;cartilage derived inhibitor; carzelesin; casein kinase inhibitors(ICOS); castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; 15 cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin 13;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin 10deslorelin; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol; dioxamycin; diphenyl spiromustine; discodermolide;docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;eflornithine; elemene; emitefur; epirubicin; epothilones; epithilones;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide; etoposide 4′-phosphate (etopofos);exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol; irinotecan;iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mithracin;mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxinfibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim; monoclonal antibody, human chorionic gonadotrophin;monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multipledrug resistancegene inhibitor, multiple tumor suppressor 1-basedtherapy; mustard anticancer agent; 15 mycaperoxide B; mycobacterial cellwall extract; myriaporone; N-acetyldinaline; N-substituted benzamides;nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin;nartograstim; nedaplatin; nemorubicin; neridronic acid; neutralendopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxideantioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone;oligonucleotides; onapristone; ondansetron; oracin; oral cytokineinducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxelanalogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; podophyllotoxin; porfimer sodium;porfiromycin; propyl bis-acridone; prostaglandin J2; proteasomeinhibitors; protein A-based immune modulator; protein kinase Cinhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;sarcophytol A; Sargramostim; Sdi 1 mimetics; semustine; senescencederived inhibitor 1; sense oligonucleotides; signal transductioninhibitors; signal transduction modulators; single chain antigen bindingprotein; sizofuran; sobuzoxane; sodium borocaptate; sodiumphenylacetate; solverol; somatomedin binding protein; sonermin; 5sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stem cell inhibitor; stem-cell division inhibitors;stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactiveintestinal peptide antagonist; suradista; suramin; swainsonine;synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide;tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium;telomerase inhibitors; temoporfin; temozolomide; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thalidomide;thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin;thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone;tin ethyl etiopurpurin; tirapazamine; titanocene dichloride; topotecan;topsentin; toremifene; totipotent stem cell factor; translationinhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate;triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors;tyrphostins; UBC inhibitors; ubenimex urogenital sinus-derived growthinhibitory factor; urokinase receptor antagonists; vapreotide; variolinB; vector system, erythrocyte gene therapy; velaresol; veramine;verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;zanoterone; zeniplatin; zilascorb; zinostatin stimalamer. Anti-cancersupplementary potentiating agents include, but are not limited to,Tricyclic anti-depressant drugs (e.g., imipramine, desipramine,amitryptyline, clomipramine, trimipramine, doxepin, nortriptyline,protriptyline, amoxapine and maprotiline); non-tricyclic anti-depressantdrugs (e.g., sertraline, trazodone and citalopram); Ca₂₊ antagonists(e.g., verapamil, nifedipine, nitrendipine and caroverine); Calmodulininhibitor (e.g. prenylamine, trifluoroperazine and clomipramine);Amphotericin B; Triparanol analogues (e.g. tamoxifen); antiarrhythmicdrugs (e.g., quinidine); antihypertensive drugs (e.g. reserpine); Thioldepleters (e.g., buthionine and sulfoximine) and Multiple DrugResistance reducing agents such as Cremaphor EL. The compounds of theinvention also can be administered with cytokines such as granulocytecolony stimulating factor.

Radioactive agents include but are not limited to Fibrinogen I 125;Fludeoxyglucose F18; Fluorodopa F 18; Insulin I 125; Insulin I 131;Iobenguane I 123; Iodipamide Sodium I 131; Iodoantipyrine I 131;Iodocholesterol I 131; Iodohippurate Sodium I 123;Iodohippurate-23-Sodium I 125; Iodohippurate Sodium I 131; Iodopyracet I125; Iodopyracet I 131; Iofetamine Hydrochloride I 123; Iomethin I 125;Iomethin I 131; Iothalamate Sodium I 125; Iothalamate Sodium I 131;Iotyrosine I 131; Liothyronine I 125; Liothyronine I 131; MerisoprolAcetate Hg 197; Merisoprol Acetate-Hg 203; Merisoprol Hg 197;Selenomethionine Se 75; Technetium Tc 99m Atimony Trisulfide Colloid;Technetium Tc 99m Bicisate; Technetium Tc 99m Disofenin; Technetium Tc99m Etidronate; Technetium Tc 99m Exametazime; Technetium Tc 99mFurifosmin; Technetium Tc 99m Gluceptate; Technetium 99m Lidofenin;Technetium Tc 99 mm Mebrofenin; Technetium Tc 99m Medronate;TechnetiumTc 99m Medronate Disodium; Technetium Tc 99m Mertiatide;Technetium Tc 99m Oxidronate; Technetium Tc 99m Pentetate; Technetium Ic99m Pentetate Calcium Trisodium; Technetium Tc 99m Sestamibi; TechnetiumTc 99m Siboroxime; Technetium Tc 99m Succimer; Technetium Tc 99m SulfurColloid; Technetium Tc 99m Teboroxime; Technetium Tc 99m Tetrofosmin;Technetium Tc 99m Tiatide; Thyroxine I 125: Thyroxine I 131; TolpovidoneI 131; Triolein I 125; Triolein I 131.

The compounds of the instant invention are efficacious in the treatmentand/or prevention of a broad range of cancers. Such cancers include butare not limited to lung cancer, bladder cancer, melanoma, bladdercarcinoma, pancreatic cancer, breast cancer.

In one aspect, the invention provides methods for the treatment ofcancer. “Cancer” as used herein refers to an uncontrolled growth ofcells which interferes with the normal functioning of the bodily organsand systems. Cancers which migrate from their original location and seedvital organs can eventually lead to the death of the subject through thefunctional deterioration of the affected organs. Carcinomas aremalignant cancers that arise from epithelial cells and includeadenocarcinoma and squamous cell carcinoma. Sarcomas are cancer of theconnective or supportive tissue and include osteosarcoma, chondrosarcomaand gastrointestinal stromal tumor. Hematopoietic cancers, such asleukemia, are able to outcompete the normal hematopoietic compartmentsin a subject, thereby leading to hematopoietic failure (in the form ofanemia, thrombocytopenia and neutropenia) ultimately causing death. Aperson of ordinary skill in the art can classify a cancer as a sarcoma,carcinoma or hematopoietic cancer. Cancer, as used herein, includes thefollowing types of cancer, breast cancer, biliary tract cancer; bladdercancer; brain cancer including glioblastomas and medulloblastomas;cervical cancer; choriocarcinoma; colon cancer; endometrial cancer;esophageal cancer; gastric cancer; hematological neoplasms includingacute lymphocytic and myelogenous leukemia; T-cell acute lymphoblasticleukemia/lymphoma; hairy cell leukemia; chromic myelogenous leukemia,multiple myeloma; AIDS-associated leukemias and adult T-cell leukemialymphoma; intraepithelial neoplasms including Bowen's disease andPaget's disease; liver cancer; lung cancer; lymphomas includingHodgkin's disease and lymphocytic lymphomas; neuroblastomas; oral cancerincluding squamous cell carcinoma; ovarian cancer including thosearising from epithelial cells, stromal cells, germ cells and mesenchymalcells; pancreatic cancer; prostate cancer; rectal cancer; sarcomasincluding leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma,and osteosarcoma; skin cancer including melanoma, Kaposi's sarcoma,basocellular cancer, and squamous cell cancer; testicular cancerincluding germinal tumors such as seminoma, non-seminoma (teratomas,choriocarcinomas), stromal tumors, and germ cell tumors; thyroid cancerincluding thyroid adenocarcinoma and medullar carcinoma; and renalcancer including adenocarcinoma and Wilms tumor. Other cancers will beknown to one of ordinary skill in the art.

The compounds may be in the form of the carboxylic acid and/or theirsalts. Salts include but are not limited to organic and inorganic salts,for example alkali-metal salts, such as sodium, potassium and lithium;alkaline-earth metal salts, such as magnesium, calcium or barium;ammonium salts; basic amino acids such as lysine or arginine; andorganic amines, such as dimethylamine or pyridine. Preferably, the saltsare tartrate and will be hydrochloride salts. The salts may be mono- ormulti-valent salts, such as monosodium salts and di-sodium salts. Thesalts may also be solvates including ethanol solvates.

The compounds described herein can be readily prepared synthetically bymethods described herein. For example, the compounds may be prepared asin Example 1. Other methods of preparation are known to those skilled inthe art and are found, for example in Synthesis of diverse analogues ofOenostacin and their antibacterial activities (Vandana, Bioorganic &Medicinal Chemistry 15 (2007) 518-525); A Simple RegioselectiveDemethylation of p-Aryl Methyl Ethers Using AluminumChloride-Dichloromethane System (Negi, Synthetic Communications, 35:15-21, 2005); Antiplatelet Activities of Newly Synthesized Derivativesof Piperlongumine (Park, Phytother. Res. 22, 1195-1199 (2008)); On thestructure of Pipertine and a synthesis of dihydropiplartine (Joshi,Tetrahedron Letters No. 20, pp. 2395-2420, 1968); Synthesis andMolecular Structure of Piplartine (Boll, Tetrahedron Letters No. 40, pp.171-175, 1984); Isolation, Synthesis and Evolutionary Ecology of PiperAmides: June 2004 (Dyer); Inter- and Intraspecific Compararisons ofAntiherbivore Defenses in Three Species of Rainforest Understory Shrubs(Fincher, J Chem Ecol (2008) 34: 558-557). The contents of thesereferences and these methods are incorporated by reference in theirentirety.

Salts of the present compound may be made by methods known in the art.For example, sodium salts may be made by dissolving the compound inethanol and adding aqueous sodium hydroxide. Hydrochloride and Tartratesalts are prepared as described in Examples 1 and 2.

Scheme I represents the preparation of Compound 1 and its tartaric acidsalt.

Another embodiment is a method of preparation of the compounds of theinstant invention. In yet another embodiment, the preparation of therepresentative compounds of the instant invention is represented byScheme II:

Mechanism

Without being bound to any particular theory, the compounds of thepresent invention exert their therapeutic effect by reducing oxidativestress and thereby reducing damage to DNA in normal cells whileincreasing ROS levels in cancer cells. The resulting effect of exposureto Reactive oxygen species (ROS) is often changes in celldifferentiation and finally, over a prolonged period, apoptosis. Undernon-stressed conditions, GSTP1 inhibits JNK phosphorylation bysequestering the JNK-c-JUN complex. Stressor triggers oligomeraizationof GSTP1 and results in dissociation of the JNK-c-JUN complex. JNK canthen become phosphorylated and activate downstream kinase andtranscription factors.

Reactive oxygen species (ROS) have been shown to be increased in, forexample, EJ Bladder Carcinoma cells, Breast Carcinoma cells, and removalof GSTJI has been shown to block the increase in ROS. SP2007 has beenshown to increase ROS in cancer cells and causes apoptosis. Othercompounds of this invention have been shown to be efficacious in vivoagainst pancreatic cancer cells, breast epithelium and EJ Bladder cancercells.

Furthermore, compounds of the instant invention are superior to thetraditional Piper longum parent molecule in that the compounds arehighly soluble. For example whereas the parent Piper longum can dissolveonly in quantities of 0.1 mg/ml in water, much larger quantities ofcompounds of the present invention are soluble in water. For example,the tartrate salt of compound one of the present invention is soluble at100 mg/ml of water.

Pharmaceutical Forms

The administration compositions may alternately be in the form of asolid, such as a tablet, capsule or particle, such as a powder orsachet. Solid dosage forms may be prepared by mixing the solid form ofthe compound with the solid form of the active agent. Alternately, asolid may be obtained from a solution of compound and active agent bymethods known in the art, such as freeze drying, precipitation,crystallization and solid dispersion.

The amount of compound used in an administration composition of thepresent invention is an amount effective to accomplish the purpose ofthe particular compound. However, the amount can be less than thatamount when the composition is used in a dosage unit form because thedosage unit form may contain a plurality of compound compositions or maycontain a divided pharmacologically, biologically, therapeutically, orchemically effective amount. The total effective amount can then beadministered in cumulative units containing, in total, an effectiveamount of the active agent.

The total amount of compound to be used can be determined by methodsknown to those skilled in the art.

The presently disclosed compounds may be in any dosage form known tothose skilled in the art, particularly suitable for oral, intranasal,sublingual, intraduodenal, subcutaneous, buccal, intracolonic, rectal,vaginal, mucosal, pulmonary, transdermal, intradermal, parenteral,intravenous, intramuscular, intrathecal, intraperitoneal and ocularadministrations, as well as traversing the blood-brain barrier. Thecompounds may also be prepared for injections, either by infusion into avein or artery or injected into the peritoneum, bladder, or directlyinto tumors. Topical preparations such as creams, ointments, gels,lotions or transdermal patches are contemplated dosage forms.

Dosage unit forms can also include any one or combination of excipients,diluents, disintegrants, lubricants, plasticizers, colorants,flavorants, taste-masking agents, sugars, sweeteners, salts, and dosingvehicles, including, but not limited to, water, 1,2-propane diol,ethanol, olive oil, or any combination thereof.

The compounds and compositions of the subject invention are useful foradministering biologically or chemically active agents to any animals,including but not limited to birds such as chickens; mammals, such asrodents, cows, pigs, dogs, cats, primates, and particularly humans; andinsects.

The compounds of the invention can be administered to animal and man,directly or together with a vehicle commonly used. The dose form is notparticularly limited, and is selected appropriately as needed on use,including oral drugs such as tablets, capsules, granules, grains andpowder, or non-oral drugs such as injection and suppository.

The oral drugs are prepared by ordinary methods, using starch, lactose,sucrose, mannitol, carboxymethylcellulose, corn starch, or inorganicsalts.

In the drugs of this type, use can be made of a binder, a disintegrator,a surfactant, a lubricant, a fluidity-promoting agent, a flavor, atinction, a perfume and the like, in addition to the vehicle mentionedabove. Non-limiting examples of some of these substances are presentedbelow:

Binder: Starch, dextrin, powdered acasia, gelatin, hydroxypropylstarch,methylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose,crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, andmacrogol.

Disintegrator: Starch, hydroxypropylstarch, carboxymethylcellulosesodium, carboxymethylcellulose calcium, carboxymethylcellulose, andlow-substituted hydroxypropylcellulose.

Surfactant: Sodium laurylsulfate, soybean lecithin, succharose fattyacid ester, and polysorbate 80.

Lubricant: Talc, waxes, hydrogenated vegetable oil, succharose fattyacid ester, magnesium stearate, calcium stearate, aluminum stearate, andpolyethylene glycol.

Fluidity-Promoting Agent: Light anhydrous silicic acid, dry aluminumhydroxide gel, synthetic aluminum silicate, and magnesium silicate.

The compounds of the present invention can also be administered in theform of suspension, emulsion, syrup or elixir. These forms of drugs mayalso contain flavor, perfume and tinction.

The non-oral drugs can be prepared by ordinary methods, and use may bemade of an attenuant such as distilled water for injection,physiological saline, aqueous solution of glucose, vegetable oil forinjection, sesame oil, peanut oil, soybean oil, corn oil, propyleneglycol, or polyethylene glycol. If necessary, germicide, preservative,and stabilizer may be added. The non-oral drugs can be filled in a vialor the like and frozen, and then be removed of water by the ordinaryfreeze-dry technique. A liquid drug can be reformulated from thefreeze-dried drug immediately before administration. Further, anisotonic, a stabilizer, a preservative, an antiseptic, a sedative, andthe like may be added.

The compositions comprising the compounds have utility in the treatmentof cancer.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate the invention without limitation. Allparts are given by weight unless otherwise indicated.

EXAMPLE 1

Compound Preparation

1a. Preparation of Compound 1 and its Tartaric Acid Salt.

Scheme I represents the preparation of Compound 1 and its tartaric acidsalt.

Preparation of BPS-02083-01

To a stirred solution of Piperlongumine (5.60 g, 17.6 mmol) in anhydrousDCM was added AlCl3 (23.3 g, 174 mmol) at 28° C. AlCl₃ cannot becompletely dissolved in the solution and the red suspension became ayellow suspension while stirred at 28° C. for 15 min. Saturated NaHCO31was added and the mixture was extracted with dichloromethane (150 mL*2).The combined organic layers were washed with brine (50 mL*3), dried overanhydrous Na2SO4, concentrated in vacuo and washed withdichloromethane/petroleum ether (v/v=2:3) to give BPS-02083-01 (3.5 g,11.6 mmol, 66%) as a yellow solid. MS (ESI/FT-MS): 304 [M+H]⁺; expected304.

Preparation of Compound I

To a stirred solution of BPS-02083-01 intermediate (1.94 g, 6.4 mmol),2-morpholinoethanol (1.0 g, 7.7 mmol) and PPh3 (2.52 g, 9.6 mmol) inanhydrous dichloromethane (80 mL) was added slowly a solution of DEAD(1.67 g, 9.6 mmol) in dichloromethane (20 mL) under N2 at 0° C. Themixture was slowly warmed to room temperature and stirred overnight. Thesolvent was removed in vacuo and purified by chromatography on silicagel (petroleum ether/ethyl acetate=1:1 to 2:1) to give BPS-02083-00 (1.4g, 3.37 mmol, 53%) as a pale yellow oil. MS (ESI/FT-MS): 417 [M+H]⁺;expected 417.

Compound 1-L-tartaric acid salt.

To a solution of BPS-02083-00 [Compound 1] (4.16 g, 10.0 mmol) indichloromethane (25 mL) was added a solution of L-tartaric acid (1.50 g,10.0 mmol) in dichloromethane/methanol (10 mL). The solvent was removedin vacuo to give the L-tartaric acid salt of BPS-02083-00 (5.66 g, 10.0mmol, 100%) as a colorless solid. MS (ESI/FT-MS): 417 [M+H]⁺; expected417, same as the free base.

EXAMPLE 2

Attempted Preparation of Compound I HCL Salt

5 gram free base of Compound I (thick oil) (˜97% by HPLC). BPS-02083-00(100 mg) was dissolved in ether (2.0 mL) and cooled to −10° C. HCl inether (saturated) was added and stirred for 10 min. The solvent wasremoved (<25° C.) to give a colorless solid (BPS-02083-00-HCl). Thespectra indicated that it is not the HCl salt of BPS-02083-00. Thestructure is B (HCl addition to double bond).

EXAMPLE 3

Preparation of Representative Compounds of the Invention

The Intermediate was prepared as in Example 1 and the procedure for thede-boc step to form the by product is as follows. To a solution ofBPS-02085 (about 35 mg) in menthol (5.0 ml) was bubled HCl(g) for 15minutes at room temperature (20° C.). The solvent was removed in vacuoand the residue was purified by TLC (DCM:MA:NH3H2O=70:4:1) to giveby-product (confirmed by 1NMR and LCMS). Non-limiting example ofcompounds which may be prepared by the ad-boc method described inExample 3 are represented below.

EXAMPLE 4

Report of Representative Compounds SM Quantity Product Quantity HPLCHNMR LCMS[M + H]+ SM-00 190 mg BPS- 124 mg + 32 mg >95% Passed 30402084-01 SM-00 SM-00 9.3 mg BPS- 254 mg + 84 mg >95% Passed 304 SM-00 13mg 02084-01 SM-00 304 SM-00 176 mg 304 SM-00 190 mg 304 BPS- 56 mg BPS-7.1 mg 95.0%  Passed 417 02084-01 02083-00 BPS- 56 mg BPS- 22 mg 96.1% Passed 375 02084-01 02084-00 BPS- 96 mg BPS- 30-40 mg >90% Passed02084-01 02085-01 BPS- 30-40 mg BPS- 0 mg 02085-01 02085-00 BPS- 65 mg +36 mg BPS- 25-30 mg >90% Passed 02084-01 02086-01 BPS- 25-30 mg BPS- 0mg 02086-01 02085-00 BPS- 56 mg BPS- 42 mg 97.1%  Passed 332 02084-0102087-00

EXAMPLE 5

Effect of Compound on Pro-Survival Gene Suppression

Additional studies will demonstrate that compounds of the instantinvention have a large therapeutic window by sparing normal cells, suchas fibroblasts and keratocytes, but killing tumors cells, such as EJcells and HCT116 cells. Studies will also demonstrate that DNA in normalcells remains unaffected by compounds of the instant invention and thatthere is no increase in ROS in normal cells.

FIGS. 1-4 show in-vivo efficacy of the compounds against pancreaticcancers cells, breast epithelium and EJ Bladder Cancer Cells.

EXAMPLE 6

Antitumor Effect of SP2007 and SP830n Bladder Tumor Xenograft-BearingMice

We tested the anti-tumor effect SP2007 and SP83 in bladder tumorxenograft-bearing mice.

Four nude/nude mice weighing approximately 0.02 Kg were fasted overnightand anestatized with Avertin (2,2,2, Tribromoethanol), 250 mg/kg, bodyweight; 1P injection. A total 2×106 EJ cells (acquired from Japanesecellbank) were implanted subcutaneously on opposite site flanks in eachof four nude/nude mice in each treatment group. Mice were fed and givenwater ad lib. When tumor masses grew to approximately 2 to 5 mm indiameter, control vehicle, SP2007 or SP83 were administeredintraperitoneally (total 2 mg/kg) every 24 hours for 25 days. Anti-tumoreffects were observed in SP2007 and SP83 administered tumor mice, ascompared to control DMSO-administered tumor mice. Results are shown inFIG. 5.

Although this invention has been described with a certain degree ofparticularity, it is to be understood that the present disclosure hasbeen made only by way of illustration and that numerous changes in thedetails of construction and arrangement of parts may be resorted towithout departing from the spirit and the scope of the invention. Manyvariations of the present invention will suggest themselves to thoseskilled in the art in light of the above detailed description. All suchobvious variations are within the fully intended scope of the appendedclaims.

1. A compound or a pharmaceutically acceptable salt thereof, wherein thecompound is selected from:


2. A pharmaceutical composition comprising one or more compounds ofclaim 1 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 3. The pharmaceutical compositionof claim 2, further comprising one or more chemotherapeutic agents.
 4. Akit comprising a pharmaceutical composition comprising a compound ofclaim 1 or a pharmaceutically acceptable salt thereof, and instructionsfor preparation and/or administration of the pharmaceutical composition.5. The kit of claim 4, further comprising one or more chemotherapeuticagents.
 6. A method for, delaying an onset of, reducing a risk ofdeveloping or worsening of, relieving or alleviating a symptom of, orrelieving or alleviating an intensity or duration of a manifestation ofa cancer in a subject, the method comprising: administering to a subjectin need thereof a compound of claim 1 or a pharmaceutically acceptablesalt thereof, wherein the cancer is selected from the group consistingof a pancreatic cancer, a breast cancer, and a bladder cancer.
 7. Themethod of claim 6, comprising inhibiting further growth of the cancer,wherein the cancer is selected from the group consisting of a pancreaticcancer, a breast cancer, and a bladder cancer.
 8. The method of claim 6comprising administering to the subject from about 2.5 mg/kg to about100 mg/kg of a compound of claim 3, or a pharmaceutically acceptablesalt thereof.
 9. A method for inhibiting cell proliferation, the methodcomprising: contacting a cell with a composition comprising a compoundof claim 1, or a pharmaceutically acceptable salt thereof, to inhibitthe proliferation of the cell, wherein the cell is selected from thegroup consisting of a pancreatic cancer cell, a breast cancer cell, anda bladder cancer cell.
 10. A method for increasing apoptosis of a cellor in a population of cells, the method comprising: contacting the cellor population of cells with a composition comprising a compound of claim1, or a pharmaceutically acceptable salt thereof, to increase apoptosisin the cell or population of cells, wherein the cell or population ofcells is selected from the group consisting of a pancreatic cancer cell,a population of pancreatic cancer cells, a breast cancer cell, apopulation of breast cancer cells, a bladder cancer cell, and apopulation of bladder cancer cells.
 11. A method for increasing p53activity in a cell or population of cells, the method comprising:contacting the cell or population of cells with a composition comprisinga compound of claim 1, or a pharmaceutically acceptable salt thereof, toincrease p53 activity in the cell or population of cells.
 12. Thecompound of claim 1, wherein said pharmaceutically acceptable salt isselected from tartrate and hydrochloride.